Ketoconazole is a drug used in the management and treatment of fungal infections. As a dioxolane imidazole, ketoconazole inhibits sterolbiosynthesis in the fungal membrane. This inhibition could deprive the fungal cell of its protective sterol membrane, making  ketoconazole widely accepted and used as a broad-spectrum drug to treat mycotic keratitis.

Pharmacokinetics

Ketoconazole is a weak dibasic agent and requires acidity for dissolution and absorption. Its pharmacokinetics in humans has been widely studied and characterized. It reaches its maximum plasma concentration at 1 -2 h and exhibits a biphasic elimination of 2 h during the first 10 h and 8 h thereafter. CYP3A4 is the major enzyme involved  in the metabolism of ketoconazole. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings by hepatic microsomalenzymes. In addition, oxidative O-dealkylation and aromatic hydroxylation do occur. Many drug-drug interaction studies of ketocona-zole in vitroand in vivohuman systems have been reported, and such information is well documented. 

Ketoconazole has also been recognized as a specific CYP3A4/5 inhibitor and a strong clinical CYP3A4 inhibitor, as well as an inhibitor of P-gp, BCRP, OATPs, OAT3, OCT2, and MATEs transporters, clinical P-gp inhibitor for drug-drug  interaction  studies recommended by regulatory agencies. Orally administered ketoconazole is limited in clinical use due to  metabolism-related  hepatotoxicity. N-deacetyl  ketoconazole  (DAK), as aprimary metabolite of ketoconazole, is believed to undergo metabolism through flavin-containing monooxy-genase (FMO) and may be transformed into a potentially toxic dialdehyde. Rodriguez et al. studied the toxicity of DAK and demonstrated that it was more metabolically cytotoxic than ketoconazole. Afterwards, Haegler et al. studied the mitochondrial toxic effects of ketoconazole at concentrations easily reached in vivo. They found that cytotoxicity and adenosine triphosphate(ATP) depletion were more pronounced in cells with mitochondrial damage. In July,2013, the US FDA released a safety announcement regarding the use of oral ketoconazole tablets and their potentialadverse drug reactions. It was advised that ketoconazole should not be used as a first-line treatment for fungal infections due to the risk of potentially serious drug-drug inter-actions. The European Medicines Agency had  also proposed limiting the use of oral ketoconazole in fungal infections due to the same risk. 

Metabolism

Although the metabolism of ketoconazole after oral administration in humans is well studied, it is not well explored in the eye in any preclinical species or humans. In rats, ketoconazole has been well  studied as a substrate in vitrosystem and in vivosystems or as a rat  CYP3A inhibitor in vitrosystems and in vivosystems. Cirello et al. reported that in rat, rabbit, and human ocular and liver S9 fractions, eleven metabolites were identified, six metabolites were found in rat ocular, whereas eight were present in rabbit and human ocular S9 fractions. Three more metabolites were found in rat liver than in rat ocular S9 fractions. Metabolic pathways in rabbit and human ocular fractions suggested the formation of reactive intermediates in rabbit and human liver, and ocular S9 incubations. Bioactivation was found to occur via iminium ion in both human and rabbit ocular S9 fractions, and the reactive intermediates were identified usingpotassium cyanide  trapping methodology.

Reference

[1] JIANG PU. Pharmacokinetics and metabolism of ketoconazole after single ocular instillation in Sprague-Dawley rats.[J]. ADMET and DMPK, 2024, 12 6: 943-955. DOI:10.5599/admet.2387.